Method of Administering Sotalol IV/SWITCH

ABSTRACT

Embodiments of the invention are broadly drawn to methods for determining an optimum dose of an antiarrhythmic drug, for example sotalol. In particular, the method involves titrating the dose of the drug gradually to determine the optimum plasma concentration for a patient, whether the patient has normal or abnormal renal function.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/003,297, filed 26 Aug. 2020, which is a continuation of U.S. patentapplication Ser. No. 16/376,706, filed 5 Apr. 2019 (now U.S. Pat. No.10,799,138), which claims the benefit of U.S. Provisional ApplicationNo. 62/652,943, filed Apr. 5, 2018. The entirety of these patentdocuments is incorporated herein.

BACKGROUND OF THE INVENTION

Congenital long-QT syndrome is a genetic disorder encompassing a familyof mutations that can lead to aberrant ventricular electrical activity.These genetic mutations are called “channelopathies”; they are theresponsible genes that encode for protein channels that regulate theflow of sodium, potassium, and calcium ions in and out of the cardiacmyocyte. The result of these mutations is an increased risk ofventricular arrhythmia, specifically torsade de pointes that can lead tosyncope, aborted cardiac arrest, and sudden cardiac death. Acquiredlong-QT and secondary arrhythmias can result from cardiac ischemia,bradycardia and metabolic abnormalities such as low serum potassium orcalcium concentration.

Acquired long-QT can also result from treatment with certainmedications, including antibiotics, antihistamines, general anesthetics,and, most commonly, antiarrhythmic medications. (Zipes D P, Am. J.Cardiol. v59, pp6E-31E, 1987). Indeed, many promising drugs for treatinga plethora of different diseases have been abandoned in the early stagesof drug testing because of adverse side effects related to causingacquired long-QT.

Cardiac arrhythmias are a common cause of morbidity and mortality,accounting for approximately 11% of all natural deaths (e.g., see KannelW B, Kannel C, Paffenbarger R S Jr, Cupples L A., “Heart rate andcardiovascular mortality: the Framingham Study” Am Heart J. v113, no.6,pp1489-94, June 1987, hereinafter Kannel 1987; and Willich S N, Stone PH, Muller J E, Tofler G H, Crowder J, Parker C, Rutherford J D, Turi ZG, Robertson T, Passamani E, et al., “High-risk subgroups of patientswith non-Q wave myocardial infarction based on direction and severity ofST segment deviation,” Am Heart J, v114, no.5, pp1110-9, November 1987,hereinafter Willich 1987). In general, presymptomatic diagnosis andtreatment of individuals with life-threatening ventriculartachyarrhythmias is poor; and, in some cases, medical managementactually increases the risk of arrhythmia and death (Cardiac ArrhythmiaSuppression Trial I I Investigators, 1992). These factors make earlydetection of individuals at risk for cardiac arrhythmias and arrhythmiaprevention high priorities.

Although long-QT (LQT) is not a common diagnosis, ventriculararrhythmias are very common; more than 300,000 United States citizensdie suddenly every year (Kannel 1987; Willich 1987) and, in many cases,the underlying mechanism may be aberrant cardiac re-polarization.

Atrial fibrillation (AF) is a type of cardiac arrythmia that can lead toblood clots, stroke, heart failure and other related complications. Atleast 2.7 million Americas live with AF. Pharmacological control ofatrial fibrillation (AF) can be achieved with class III antiarrhythmicdrugs (AADs) such as sotalol, amiodarone or dofetilide. Sotalol can beused intravenously or orally. For intravenous (IV) use, sotalol is anantiarrhythmic agent, and for oral use sotalol is for maintenance ofnormal sinus rhythm, such as for patients that have a history of normalsymptomatic atrial fibrillation or flutter. The FDA mandates in-hospitalinitiation of sotalol, especially for patients with co-morbid diseases,to reduce the risk of adverse events (AE) such as QTc-related torsadesde pointes (See Kim, 2011). In addition to maintenance of normal sinusrhythm in patients with symptomatic atrial fibrillation or atrialflutter (AF/AFL), oral sotalol is used in the acute management oflife-threatening ventricular arrhythmias as recommended by the AdvancedCardiovascular Life Support (ACLS) clinical guidelines (Neumar, 2010).

For a patient's heart electrical cycle, a QT interval (QT) is a timemeasured between a beginning of a Q wave and an end of a following Twave. Since the QT can be affected by a patient's heart rate, the QT canbe corrected (QTc) to a baseline heart-rate corrected interval based onmany factors, such as electrolyte abnormalities, a diurnal effect,autonomic fluctuations, ECG variability, and the like.

In AF treatment, oral (PO) sotalol is recommended to be initiated at adose of 80 mg twice daily, with gradual titration to 240 and 360 mg/dayas needed (e.g., oral sotalol USPI). Intravenous sotalol, a relativelynewer addition to the market, and is used as an alternative to POtherapy in patients unable to take oral sotalol (e.g., US PrescribingInformation for sotalol hydrochloride injection). The bioavailability oforal sotalol is close to 100% compared to the IV sotalol. Each dose ofIV sotalol is administered as a 5-hour infusion to mimic thepharmacokinetics of oral therapy. A boxed warning for both productsrecommends that treatment be initiated in a hospital setting thatfacilitates QTc monitoring until steady-state exposures are achieved onday 3, after 4-5 doses of sotalol administered twice daily. Thethree-day hospital stay can be a major inconvenience for healthcareprofessionals and patients alike and may significantly increase the costburden associated with length of stay.

SUMMARY OF THE INVENTION

In embodiments described herein, a method including detecting a baselineQTc of a subject, administering a first dose of an antiarrhythmic drugvia a first intravenous infusion for first duration of time, thendetermining the difference between the baseline QTc and a first QTcmeasured after the first intravenous infusion to detect a first deltaQTc. The method further includes if the first delta QTc detected is inan acceptable range of less than 20% from the baseline, thenadministering a second dose of the antiarrhythmic drug via a secondintravenous infusion for a second duration of time. If the first deltaQTc is not acceptable, then discontinuing intravenous administration andadministering any further doses of the drug orally.

In other embodiments, a method including administering a first dose ofan antiarrhythmic drug to a patient via a first intravenous infusion,infused for a 0.5 hour-2 hour time period, and administering a seconddose of the drug via a second intravenous infusion upon completion ofthe first intravenous infusion is provided herein.

BRIEF SUMMARY OF THE DRAWINGS

The present invention is illustrated by way of example, and not by wayof limitation, in the figures of the accompanying drawings and in whichlike reference numerals refer to similar elements and in which:

FIG. 1A is a block diagram that illustrates an example ECG according toan embodiment.

FIG. 1B is a table of pharmacokinetic model parameter estimates.

FIG. 2 is a graph illustrating the sotalol plasma concentrationsapproaching a steady state over many doses with the reference FDArecommended sotalol dosing regimens of 80, 120 and 160 mg BID given to a70 kg patient.

FIG. 3 is a graph illustrating a set of QTc profiles at these doselevels of FIG. 2 based on the concentration-QTc relationship.

FIG. 4 is a table of dosing strategies explored for IV-oral switch.

FIG. 5 is a flow chart illustrating a dose titration scheme to initiatesotalol in naïve patients, according to one embodiment of the presentinvention.

FIG. 6 is a table of Sotalol dosing regimens using and IV/PO switchmethod to reach Cmax,ss in patients that need to be re-stabilized onprior stable dose.

FIG. 7 is a table of Sotalol dosing regimens using and IV/IV switchmethod to reach Cmax,ss in patients that need to be re-stabilized onprior stable dose.

FIG. 8 is a table of a titration dosing regimens to reach Cmax,ss insotalol-naïve patients using a IV/PO switch method.

FIG. 9 is a graph illustrating a proposed titration method embodimentfor the 80 mg dose.

FIG. 10 is a graph illustrating a proposed titration method embodimentfor the 120 mg dose.

FIG. 11 is a graph illustrating a proposed titration design embodimentfor the 160 mg dose.

FIG. 12 is a graph illustrating multiple delta QTc profiles acrossconcentrations observed after different titration designs.

FIG. 13 is a graph illustrating a titration method embodiment for the160 mg dose in a 70 kg patient with renal impairment.

DETAILED DESCRIPTION

Embodiments of the invention are broadly drawn to methods fordetermining an optimum dose of an antiarrhythmic drug, for examplesotalol, to be administered to a subject to treat atrial fibrillation.In particular, the method involves titrating the dose of the druggradually to determine the optimum plasma concentration for a patient,whether the patient has normal or abnormal renal function.

Methods are described for dosing the antiarrhythmic drug foraccelerating achievement of steady-state maximum plasma concentration(Cmax,ss) of the therapeutic agent by intravenous administration or acombination of intravenous and oral administration. The therapeuticagent may include sotalol for treating serious abnormal heart rhythms.In the following description, for the purposes of explanation, numerousspecific details are set forth in order to provide a thoroughunderstanding of the present invention. It will be apparent, however, toone skilled in the art that the present invention may be practicedwithout these specific details. Various references are cited below. Ineach case the cited reference is hereby incorporated in its entirety asif fully set forth herein, except for terminology inconsistent with thatused herein.

The following terms as used herein have the corresponding meanings givenhere.

TABLE 1 Definitions of terms used herein LQT Long-QT syndrome, acondition in which the duration of time betweenthe onset of the QRScomplex and the termination of the T wave on the electrocardiogram (ECG)is prolonged. LQT is a risk marker for a heightened propensity for theoccurrence of specific heart beat arrhythmias. subject An organism thatis an object of a method or material, including mammals, e.g., humans,dogs, cows, horses, kangaroos, pigs, sheep, goats, cats, mice, rabbits,rats, and transgenic non-human animals. Synonyms used herein include“patient” and “animal” antiarrhythmic A drug within a class of drugsused to treat abnormal drug (AAD) heart rhythms, or arrythmias.therapeutically an amount of a therapeutic agent, which achieves aneffective intended therapeutic effect in a subject, e.g., eliminatingamount or reducing the severity of a disease or set of one or moresymptoms The full therapeutic effect does not necessarily occur byadministration of one dose and may occur only after administration of aseries of doses. Thus, a therapeutically effective amount may beadministered in one or more treating taking steps to obtain beneficialor desired results, including clinical results, such as alleviating orameliorating one or more symptoms of a disease; diminishing the extentof disease; delaying or slowing disease progression; ameliorating andpalliating or stabilizing a metric (statistic) of disease. “Treatment”refers to the steps taken. naive A subject who has not receivedtreatment with the therapeutic agent previously. maintenance An oral orIV dose, given following IV titration or loading, dose at regularintervals.

Overview

Applicants have identified an accelerated dosing regimen for anantiarrhythmic drug allowing achievement of steady-state maximum plasmaconcentration (Cmax,ss) of the antiarrhythmic drug by intravenous andoral administration. The methods described herein may be used to titratedosage for a particular patient based on their tolerability for thedrug, whether the patient is naïve to the drug or whether the patienthas stopped taking the drug for some time and a maintenance dose is tobe re-initiated in the patient.

The methods described herein take into consideration the renal health ofthe patient, wherein dosages vary based on whether the patient hasnormal or abnormal renal health (renal impairment, for example).

The dosing regimen described in the method embodiments herein provides atitration of the drug in order to safely increase the dose of the drugto reach a target maintenance dose in a shorter period of time than theexisting standard of care which includes a 3-day hospital stay to reachthe target maintenance dose for a patient. Existing methods forachieving a target maintenance dose in a patient includes treating withoral (PO) sotalol, initiated at a dose of 80 mg twice daily, withgradual titration to 240 mg and 360 mg/day as needed.

In at least a first embodiment, a method according to the inventionincludes detecting a baseline QTc (corrected QT) level in a subject toreceive treatment. In the method a first dose of an antiarrhythmic drugis administered by way of a first intravenous infusion for a firstperiod of time. Following the first IV infusion, a first QTc measurementis taken, and a change from the baseline to the first QTc (a first deltaQTc) is detected in order to determine whether it is safe to proceedwith additional IV infusions to increase the dose of the drug for thesubject. If the change in QTc from baseline is within an acceptablerange, and it is determined safe to proceed, then a second dose of thedrug is administered via a second IV infusion for a second duration oftime. If it is not determined that it is safe to proceed, and the firstdelta QTc is outside an acceptable range, any further doses of the drugare administered orally, and the patient is monitored by a physician.Acceptable ranges for the first delta QTc include +/−20% from thebaseline QTc measurement.

If following the second IV infusion, a second QTc measurement is taken,and the second delta QTc is in an acceptable range (+/−20% from thebaseline QTc measurement), a third intravenous infusion dose of the drugis administered for a third duration of time. If the second delta QTc isnot in an acceptable range, the patient is administered any furtherdoses orally. An unacceptable delta QTc includes a value that is lessthan −20% from QTc baseline or greater than +20% from the baseline QTc.If at the end of the third intravenous infusion, the third delta QTc isacceptable (within +/−20% of the baseline QTc), any further doses of thedrug may be administered orally, or alternatively, an additionalintravenous infusion may be provided to the patient.

For patients suffering with abnormal renal function, the oral dosesadministered may be decreased, and/or the time between the intravenousdose and the oral dose or between subsequent oral maintenance doses maybe lengthened. For example, the oral maintenance doses may beadministered every 24 hours instead of every 12 hours for patients withrenal impairment or abnormal renal function. In some instances, withpatients having abnormal renal function, the IV doses administered maybe decreased in amount or strength to account for any renal impairment.

DETAILED DESCRIPTION

FIG. 1A is a block diagram that illustrates an example normal ECG trace120 for a single heartbeat, according to an embodiment. Time increasesto the right and electric field strength increases vertically. The ECGtrace 120 shows several labeled features including an initial increase P101 in electric field followed in sequence by a dip Q 103, a spike R105, another dip S 107 and a final increase T 109. Certain intervals aredefined by these labeled features, including PR interval 121 frombeginning of P 101 to beginning of Q 103, QRS complex from beginning ofQ 103 to end of S 107, ST segment from end of S 107 to beginning of T109, and QT interval from beginning of Q 103 to end of T 109. An RRinterval refers to a time interval from the peak of R 105 to the peak ofR in the next heartbeat, not shown. A rate corrected QT (abbreviatedQTc) is given by the ratio of the QT interval to the square root of theRR interval. LQT occurs when the QT interval, or QTc, is substantivelyprolonged relative to normal variations.

The dosing method according to the current embodiment allows switchingfrom IV to PO, and alternatively from one IV dosing to another IVdosing, such that the dosing method is configured to allow forsubstantial hospital cost savings and increased convenience.

The dosing methods described herein do not increase risk to a patient.This can be substantiated with the abundant literature on IV sotalol, inwhich IV infusions as rapid as 5 minutes were safely administered (Ho etal, 2004, 2005). Sotalol 1.5 mg/kg IV over 5 minutes is recommended bythe ACLS guidelines in the treatment of stable-wide complex tachycardiasin adult VT [Neumar 2010]. This recommendation was developed on thebasis of various studies that evaluated the safety and efficacy of rapidinfusions, reporting only mild to moderate adverse events, such ashypotension and dyspnea associated with the beta-blocking capabilitiesof sotalol [Jordaens 1991, Sung 1994], and QT prolongation [Nademanee1985, Joardens 1991]. Further, a large meta-analysis of the risk ofTorsades de Pointes in patients treated with rapid IV sotalol infusionsshowed minimal risk for patients treated with a single IV infusion ofsotalol as compared to oral therapy [Marill 2011]. FIGS. 12 and 13 showthat the risk of QTc prolongation is no more than 30 msec across all thedoses in the proposed dosing regimens.

The dosing method according to one embodiment is generally applicable inpatients with both normal or impaired renal function with a slightmodification, as shown in FIGS. 5A, 6, and 7 . The method and dosingregimens of the embodiments herein allow clinicians to cease infusionsat any time if the QTc changes such that the QTc following any IVadministration compared to the subject's baseline QTc is unacceptablyprolonged. This flexibility is not available for an ingested tablet, forwhich three days of hospital monitoring is required to assess the QTcprolongation risk, resulting in increased cost of treatment.

Pharmacokinetic Model

FIG. 1B is a chart showing a pharmacokinetic (PK) model including anadjustment with data from both treatment arms for a reduced totaladministered dose of 62 mg. A 2-compartment model using first orderabsorption (with lag time) and elimination following IV and POadministration for fitted sotalol is shown in FIG. 1B. The relativebioavailability of IV to PO sotalol was also evaluated.

FIG. 2 is a graph illustrating the sotalol plasma concentrationsapproaching a steady state over many doses with the reference FDArecommended sotalol dosing regimens of 80, 120 and 160 mg BID given to a70 kg patient. The 80 mg BID dose is show by the bottom line in thegraph, the 120 mg BID dose is shown by the middle line in the graph, andthe 160 mg BID dose is shown by the top line in the graph.

FIG. 3 is a graph illustrating a set of QTc profiles at the dose levelsshown in FIG. 2 based on the concentration-QTc relationship. The 80 mgBID dose is show by the bottom line in the graph, the 120 mg BID dose isshown by the middle line in the graph, and the 160 mg BID dose is shownby the top line in the graph.

FIG. 4 is a table of dosing strategies explored for IV-oral switch, forsotalol naïve patients as described in the methods for dosing herein.

FIG. 5 is a flow chart 500 illustrating a brief overview of a method fordosing an antiarrhythmic drug to initiate sotalol in sotalol-naïvepatients, according to one embodiment. Initiation of the treatmentincludes titrating by IV loading 510, including, for example, bymeasuring a baseline QTc and then initiating a first dose administrationof an antiarrhythmic drug by a first intravenous infusion for a firstperiod of time. At the end of the IV infusion, a QTc measurement istaken, and is compared with the baseline QTc. If the change in QTc iswithin an acceptable range 514, a second dose of the drug isadministered by IV infusion for a second period of time 516. Once thetarget maintenance dose has been reached, or, once the change in QTcmeasurement is found not to be within acceptable range, all IV infusionsare discontinued, and the patient may further be administered oral dosesof the drug only. Thus, the method includes titrating IV drug to allowsafe dose escalation to the target oral maintenance dose, based onchange from baseline in observed QT to the end of infusion (FIG. 5 ).

Effect of Sotalol Concentration on QTc

One embodiment of the method includes determining the change in QTcprolongation due to sotalol (e.g., sotalol-induced QTc prolongation)compared to the measured baseline QTc. QT prolongation risk is based onthe relationship (e.g., provided in an FDA clinical pharmacology review)in which QTc=Baseline QTc+Slope×Concentration for Betapace tablets.Sotalol plasma concentration directly relates to QTc prolongation. Thus,one measure for evaluating safety of the method is QTc prolongation.

The method includes determining and recording a Baseline QTc prior tosotalol treatment, such as immediately prior to sotalol treatment.Concentration generally refers to observed sotalol plasma concentrationsafter initiation of the method, and Slope is generally a unit increasein QTc from Baseline QTc for a unit change in sotalol concentration. Forexample, the method of one embodiment determines Slope when determiningthe change of the QT interval from the baseline QTc. As a furtherexample, Median Baseline QTc reported in clinical trials was 405 msecand the slope of the concentration QTc relationship was 0.0158msec/ng/mL.

Dose Optimization

The method embodiments described herein are configured to optimize thedose and route of an antiarrhythmic drug to reduce the hospital lengthof stay by accelerating Cmax,ss to earlier times, e.g., on Day 1,without compromising the patient's safety. The method according tocurrent embodiment is further configured to:

a. Define an IV loading dose and oral maintenance strategy tore-stabilize patients who were on prior stable PO sotalol therapy; and

b. Define an IV dose titration scheme for sotalol-naïve patients toenable selection of a stable oral maintenance dose.

Dose Re-Stabilization Method

Generally, patients who are temporarily discontinued from oral sotaloltherapy, either due to surgery or other reasons, need to bere-stabilized to their Cmax,ss as soon as possible. Re-initiationtypically involves approximately 3 hospital days of monitored oral drugadministration of the antiarrhythmic drug before the target dose Cmax,ss is achieved. FIG. 2 provides the average Cmax,ss on Day 3 forpatients with normal renal function, based on the reference PO dose.Specifically, FIG. 2 shows the recommended sotalol dosing regimens of80, 120 and 160 mg BID given to a 70 kg patient a) as sotalol plasmaconcentrations approach steady-state after 5-6 doses; and b) for QTcprofiles at these dose levels based on the concentration-QTcrelationship, as shown in FIG. 3 .

Dose Titration for Sotalol Naïve Patients

According to one embodiment of the method, initiating the treatmentincludes titrating sotalol. Additional embodiments can further includeapplying the IV loading strategy having progressively higher titratingdoses, such as higher doses of 120 or 160 mg (e.g., target oralmaintenance doses), based on tolerability. Thus, the method includestitrating IV sotalol to allow safe dose escalation to the target oral orIV maintenance dose, based on change from baseline QTc compared to theQTc measured at the end of a given IV infusion (FIG. 5 ).

QTc Monitoring

According to another embodiment, the method includes determining the IVloading strategy according to a pharmacokinetic model, which describes arelationship between sotalol concentration and QTc prolongation. Themethod for both the re-stabilization and solatol-naïve patients (e.g.,titration) embodiments uses the methods as discussed herein, in whichthe initial sotalol IV infusion ideally does not prolong QTc beyond aclinically acceptable range (e.g., >500 msec). Thus, the method canincrease the likelihood that the calculated plasma concentrations aresafe and do not exceed Cmax,ss for each dose level. After each IVinfusion, QTc is measured and evaluated as being acceptable before afollow-up IV infusion is administered. If the QTc after an infusion isin an unacceptable range, then the protocol is changed so that nosubsequent IV infusions are administered, and instead the protocolswitches to oral administration of a known safe dose of the drug.,Calculating the change in QTc across the range of doses can includedetermining and assuming variability between subjects in terms ofpharmacokinetic parameters of the pharmacokinetic model and theconcentration-QTc relationship.

FIGS. 9, 10, 11 are graphical illustrations of proposed titrationdesigns for the 80, 120, and 160 mg doses.

Dose Adjustments for Patients with Renal Impairment

The product label recommends once-a-day dosing in patients with mildrenal impairment (CLcr between 40 and 60 mL/min), and sotalol iscontraindicated in patients with moderate to severe renal impairment(CLcr<40 mL/min). The inventors herein evaluated once-a-day dosingregimens that would facilitate earlier Cmax,ss in mildly impairedpatients by assuming that sotalol clearance is 50% (6 L/hr) of the valueobserved in patients with normal renal function.

REFERENCE DOSE COMPARISON

The inventors evaluated the performance of the optimized dosingstrategies by comparing the proposed computer simulated dosing scenariostrategy to the reference dosing currently used in clinical practicewhich is the oral administration of 80, 120 or 160 mg BID.

Analyses

Evaluating dosing scenarios according to the current embodiment includedsimulation calculations. For example, for a re-stabilization embodiment,evaluating dosing scenarios included applying average pharmacokineticparameters for a 70 kg patient (FIG. 2 ) in simulations using NONMEM(version 7.3; ICON, Ellicott City, Md.). Post-processing of results wereperformed with R (https://www.r-project.org/). Evaluating dosingscenarios further included administering an initial IV loading dosebased on labeled dose-titration rrecommendations. Thus, evaluatingincluded using Monte Carlo simulations in 1,000 patients with a mean(SD) body weight of 70 kg. The variability in body weight and the randomvariability between subjects allowed the calculation of QTc prolongationfor a range of sotalol concentrations. Quantitative metrics and graphsof time course of plasma sotalol concentrations, or the change in QTc,were used to compare the various dosing scenarios tested with thereference dosing, with a goal of ensuring that Cmax,ss was not exceeded,and with minimal risk of QTc prolongation.

Sotalol Pharmacokinetics

The results of evaluating the dosing scenarios according to a currentembodiment indicated that the mean terminal half-life (t½) of sotalol is12 hours in adults, and it takes about 2.5 to 3 days to achievesteady-state plasma concentrations. FIG. 1 shows the pharmacokineticmodel parameters published in the FDA clinical pharmacology review usedto develop the dosing method embodiments described herein. Based onthese parameters, it takes about 5-6 oral doses, administered twice aday to reach Cmax,ss in a 70 kg subject with normal renal function.

Sotalol Concentration—QTc Relationship

As described above, the current embodiments of the method uses the FDA'slinear function equation as a pharmacokinetic-QTc model to assess therelationship between sotalol concentration and QT prolongation. Forexample, the linear function equation uses the three reference BID POdoses (80, 120 and 160 mg) for a 70 kg individual with normal renalfunction and baseline QT of <405 msec. The concentrations determined bythe pharmacokinetic model were those that produced an acceptableprolongation in the QTc measured after IV administration of not morethan approximately 25 msec compared to the baseline QTc.

Dose Optimization

Optimizing the dosing method for a current embodiment is furtherconfigured to accelerate dosing of Cmax,ss to as early as Day 1 (FIGS.9-11 ). For example, by optimizing the dosing method further includeddetermining the average Cmax,ss and QTc prolongation at three differentreference doses of 80 mg (FIG. 9 ), 120 mg (FIG. 10 ) and 160 mg (FIG.11 ), administered intravenously as described below. The titrationmethod embodiments shown in FIGS. 9-11 provide titration doses for 80mg, 120 mg, and 160 mg doses as described, and demonstrate Sotalolconcentrations in ng/mL during dosing. LD refers to a loading dose, andMD refers to a maintenance dose. The data of FIG. 9 shows a loading doseof Sotalol in the form of a 40 mg infused intravenous dose 910, whereinSotalol concentrations reach approximately 500 ng/ml following the 40 mgSotalol IV dose. The 40 mg IV dose is followed by an 80 mg PO Sotaloldose 912, further escalating Sotalol concentration every 12 hours asshown in FIG. 9 . Finally, the 80 mg maintenance dose 914 is shown inFIG. 9 , as provided every 12 hours thereafter, such that the Sotalolconcentration in the patient reaches approximately 800 ng/mLapproximately every 12 hours (BID) based on the maintenance dose.

FIG. 10 shows a loading dose in the form of a 40 mg Sotalol IV infusionfor one hour 1010, and a 20 mg Sotalol IV infusion over 0.5 hours 1011increasing the Sotalol concentration to nearly 800 ng/mL as shown.Following IV infusion, an oral dose (or in some embodiments this dosemay be delivered by a further IV infusion) of 120 mg Sotalol isadministered 1012, further increasing the concentration of Sotalol asshown. Finally, a maintenance dose of 120 mg Sotalol twice daily isdelivered increasing Sotalol concentrations to approximately 1200 ng/mLas provided.

FIG. 11 shows Sotalol concentrations resulting from a first IV infusionof 40 mg Sotalol for one hour 1110 followed by a second IV infusion of20 mg Sotalol for 0.5 hour 1112, followed by a third IV infusion of 20mg Sotalol infused over 0.5 hour 1114. Thereafter, a 160 mg dose ofSotalol is administered 1116, in some embodiments PO such that theSotalol concentration is shown to increase to over 1000 ng/mL Sotalolafter the first 160 mg dose. Thereafter, a maintenance dose 1118 of 160mg twice daily as otherwise described herein results in a Sotalolconcentration of approximately 1616.9 ng/mL in a patient.

FIG. 13 demonstrates Sotalol concentrations during IV loading (ng/mL),wherein a first loading dose of 40 mg IV is infused over one hour 1310,a second dose of 10 mg IV is infused over 0.5 hours 1312, and a thirdloading dose of 10 mg IV is infused over 0.5 hours. Thereafter, a doseof Sotalol of 160 mg is delivered 1316 either PO or IV, and amaintenance dose of 160 mg is delivered 1318 PO or IV twice daily tomaintain Sotalol concentrations at or above approximately 1600 ng/mL.The graphical data shows increases in the Sotalol concentration duringIV loading as described in one embodiment of a method herein.

Re-Stabilization Method

In one embodiment, an optimal dosing regimen(s) achieved Cmax,ss asearly as 4 hours after initiation of treatment on Day 1 (e.g., asdescribed in FIG. 6 ).

In one example, a patient was stabilized on an 80 mg PO BID dose beforeinterrupting the treatment. To achieve Cmax,ss for a 80 mg BID POmaintenance dose, the patient was first administered a dose of 40 mg IVsotalol infused over 2 hours. At the end of the two-hour infusion, thepatient was administered an 80 mg dose by oral administration. A secondPO dose of 80 mg was then administered 12 hours after the initiation ofthe first IV infusion, as recommended. Switching to the maintenance 80mg PO dose at the end of the first infusion resulted in Cmax,ssconcentrations of ˜800 ng/mL at Tmax (2 hours) of the PO dose,approximately 4 hours after the initiation of approximately 25 msecfirst IV infusion. This indicates that Cmax,ss, which is typicallyreached within 3-5 days using the traditional oral loading protocol, cannow likely be achieved within approximately 4 hours after initiation ofa first IV loading infusion. Similar results were observed for the 120and 160 mg oral BID doses.

FIG. 7 is a table according to one embodiment providing a schedule fordosing a patient with an antiarrhythmic drug. To achieve Cmax,ssequivalent to 75 mg IV sotalol infused over 5 hours, the patient isadministered a first 40 mg IV infusion over 2 hours, and a second 5 hourinfusion of 75 mg soon after completion of the IV loading dose (alsoherein the first IV dose), in one embodiment as shown in FIG. 7 . Insome examples described herein, the methods include administration ofthe drug by both IV and PO, or by multiple IV administrations. In someembodiments Cmax,ss is achieved within 4 hours of initiation oftreatment in a method wherein one or more IV infusions are followed byoral administration, also called a mixed dosing method, In otherembodiments, Cmax,ss is achieved within 7-14 hours after initiation ofthe first IV followed by one or more subsequent IV infusions.

Dose Titration for Sotalol Naïve Patients

FIG. 8 further describes a dose titration scheme of the currentembodiment for initiating new sotalol patients. The dose titrationscheme for initiating new sotalol patients includes analysis of manydosing scenarios (e.g., FIG. 4 ) and further includes a dosing regimenthat is generally optimized for patients that require re-stabilization(FIG. 6 ). To reach Cmax,ss earlier, the method includes applying an IVloading strategy, after a baseline QTc is measured. The IV loadingstrategy begins with administering a first 40 mg IV loading dose for 1hour, at which time the patient can be transitioned to 80 mg oralsotalol if an 80 mg BID oral maintenance dose is desired.

However, if the desired stable oral dose is 120 mg, then more than oneIV infusion is used, and the QTc is measured after each infusion andcompared to the baseline QTc to determine if it is safe to proceed. Ifthe change in QTc from baseline is within an acceptable range, thetitration may proceed by moving to the next IV infusion. In oneembodiment, wherein the subject has normal renal function, an additional(second) 20 mg IV is administered over 0.5 hours. The dose titrationscheme for initiating new sotalol patients can further include measuringthe QTc interval and if it is in an acceptable range, determining that athird 20 mg IV infusion for 0.5 hour may be given for those patientswith normal renal function to increase sotalol concentration; afterwhich the method permits a switch to 160 mg sotalol PO. After the 3rdQTc measurement, for example, the dose can be any of 80, 120 or 160 mgPO or the equivalent IV in some embodiments.

In some embodiments, QTc will be measured at the end of every 0.5 hour(or when the infusion is finished). The measurement of QTc is a quickprocedure, therefore, the subsequent infusion following QTc measurementis administered after the QTc reading is taken. In some embodiments, theIV infusion will still be connected to the patient, but the infusion maybe stopped during the QTc measurement.

If the QTc is measured, and is found to be not within an acceptablerange, no further IV administration is undertaken, and either an oralmaintenance dose of 160 mg sotalol is maintained, or the patient may bede-escalated to 120 mg maintenance dose twice daily or possibly 80 mgmaintenance dose, twice a day by oral administration. The oralmaintenance doses described herein may be initiated either 1) 12 hoursfrom the initiation of the first IV infusion, or 12 hours from thecompletion of the first IV infusion for patients with normal renalfunction, or 2) 24 hours from initiation of the first IV infusion, or 24hours from the completion of the first IV infusion for patient withabnormal renal function.

Thus, titration-based dosing according to method embodiments describedherein, is in accordance with the FDA guidelines and provides cliniciansadditional dosing control and flexibility during treatment because IVinfusion occurs in multiple steps or stages that can be interrupted andswitched to oral administration at any point if the patient is unable totolerate the infusion.

Evaluation of QT Interval Prolongation

While ensuring sotalol concentrations did not exceed Cmax,ss relative tothe reference PO doses, QT interval prolongation was also evaluated.FIG. 12 shows the change in QTc from baseline across a range ofconcentrations observed during the IV/PO switch across all three doses80, 120 and 160 mg. The maximum change in QTc observed at the highestconcentration is approximately 30 msec, a clinically acceptable rangeconsidering sotalol prolongs the QT interval as a general property ofthe drug class.

Dosing in Renally Impaired Patients

As was described above, embodiments describe methods of dosing sotalolfor patients being re-stabilized on oral sotalol therapy, oralternatively, dosing sotalol for sotalol—naïve patients (see FIGS. 6,and 7). Methods are provided for dosing sotalol for renally impairedpatients, which methods are generally similar to the embodimentsdescribed above for patients with normal renal function. Dosing sotalolfor renally impaired patients includes maintenance PO doses givenonce-a-day in accordance with the product label, and reducing by halfthe amount of sotalol administered after the initial IV infusion. Thus,some embodiments described herein allow the Cmax,ss to approximatelymatch concentrations achieved at steady-state after BID PO dosing innormal patients (see FIG. 13 ).

Antiarrhythmic Drugs

The term “antiarrhythmic drug” as used herein, includes, sotalol,dofetilide, flecainide, propafenone, amiodarone, dronedarone, oributilide among other antiarrhythmic drug known in the art. Otherclasses of drugs may also be used with the methods described herein,wherein there is an availability of an IV and oral formulation of thedrug, and minimal to no risk to the patient by loading the patient on alarger IV dose. Sotalol (Betapace) for oral administration is availableas a generic tablet from Covis Pharma By, UPsher Smith Labs, ApotexInc., among other manufacturers. Sotalol for IV administration isavailable at Altathera Pharmaceuticals.

As described herein the antiarrhythmic drugs of the some embodiments areadministered preferably either orally, preferably as solid compositions,or intravenously as a liquid composition. However, the drugs may beadministered parenterally, by inhalation spray, topically, rectally,nasally, buccally, vaginally or via an implanted reservoir. Sterileinjectable forms of the therapeutic agents may be aqueous or oleaginoussuspensions. These suspensions may be formulated according to techniquesknown in the art using suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium.

The antiarrhythmic drugs employed in some embodiments may be orallyadministered in any orally acceptable dosage form, including, but notlimited to, solid forms such as capsules and tablets. In the case oftablets for oral use, carriers commonly used include microcrystallinecellulose, lactose and corn starch. Lubricating agents, such asmagnesium stearate, are also typically added. When aqueous suspensionsare required for oral use, the active ingredient may be combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

The antiarrhythmic drugs employed in the some embodiments may also beadministered by nasal aerosol or inhalation. Such antiarrhythmic drugsmay be prepared according to techniques well-known in the art ofpharmaceutical formulation and may be prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or otherconventional solubilizing or dispersing agents.

Should topical administration be desired, it can be accomplished usingany method commonly known to those skilled in the art and includes butis not limited to incorporation of the composition into creams,ointments, or transdermal patches.

The passage of agents through the blood-brain barrier to the brain isnot desired but can be enhanced by improving either the permeability ofthe agent itself or by altering the characteristics of the blood-brainbarrier. Thus, the passage of the agent can be facilitated by increasingits lipid solubility through chemical modification, and/or by itscoupling to a cationic carrier. The passage of the agent can also befacilitated by its covalent coupling to a peptide vector capable oftransporting the agent through the blood-brain barrier. Peptidetransport vectors known as blood-brain barrier permeabilizer compoundsare disclosed in U.S. Pat. No. 5,268,164. Site specific macromoleculeswith lipophilic characteristics useful for delivery to the brain aredisclosed in U.S. Pat. No. 6,005,004.

Examples of routes of administration comprise oral, parenteral, e.g.,intravenous, intradermal, subcutaneous, inhalation, transdermal(topical), transmucosal, and rectal administration. Solutions orsuspensions used for parenteral, intradermal, or subcutaneousapplication can comprise the following components: a sterile diluentsuch as water for injection, saline solution, fixed oils, polyethyleneglycols, glycerine, propylene glycol or other synthetic solvents;antibacterial agents such as benzyl alcohol or methyl parabens;antioxidants such as ascorbic acid or sodium bisulfate; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. pH can be adjusted with acids or bases,such as hydrochloric acid or sodium hydroxide.

The parenteral preparation can be enclosed in ampoules, disposablesyringes or multiple dose vials made of glass or plastic. Therapeuticagents suitable for injection comprise sterile aqueous solutions (wherewater soluble) or dispersions and sterile powders for the extemporaneouspreparation of sterile injectable solutions or dispersions. Forintravenous administration, suitable carriers comprise physiologicalsaline, bacteriostatic water, Cremophor EL.TM. (BASF, Parsippany, N.J.)or phosphate buffered saline (PBS). In all cases, the composition mustbe sterile and should be fluid to the extent that easy syringabilityexists. It should be stable under the conditions of manufacture andstorage and must be preserved against the contaminating action ofmicroorganisms such as bacteria and fungi. The carrier can be a solventor dispersion medium containing, for example, water, ethanol, polyol(for example, glycerol, propylene glycol, and liquid polyetheyleneglycol, and the like), and suitable mixtures thereof.

The proper fluidity can be maintained, for example, by the use of acoating such as lecithin, by the maintenance of the selected particlesize in the case of dispersion and by the use of surfactants. Preventionof the action of microorganisms can be achieved by various antibacterialand antifungal agents, for example, parabens, chlorobutanol, phenol,ascorbic acid, thimerosal, and the like. In some cases, isotonic agentsare included in the composition, for example, sugars, polyalcohols suchas manitol, sorbitol, or sodium chloride. Prolonged absorption of aninjectable composition can be achieved by including in the compositionan agent that delays absorption, for example, aluminum monostearate orgelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the specified amount in an appropriate solvent with one or acombination of ingredients enumerated above, as needed, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle that contains abasic dispersion medium and other ingredients selected from thoseenumerated above or others known in the art. In the case of sterilepowders for the preparation of sterile injectable solutions, the methodsof preparation comprise vacuum drying and freeze-drying which yields apowder of the active ingredient plus any additional desired ingredientfrom a previously sterile-filtered solution thereof.

Oral compositions generally comprise an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules, e.g., gelatin capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser thatcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and comprise, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

The antiarrhythmic drugs may also be prepared in the form ofsuppositories (e.g., with conventional suppository bases such as cocoabutter and other glycerides) or retention enemas for rectal delivery.

Alternatives and Extensions

In the foregoing specification, the invention has been described withreference to specific embodiments thereof. It will, however, be evidentthat various modifications and changes may be made thereto withoutdeparting from the broader spirit and scope of the invention. Thespecification and drawings are, accordingly, to be regarded in anillustrative rather than a restrictive sense. Throughout thisspecification and the claims, unless the context requires otherwise, theword “comprise” and its variations, such as “comprises” and“comprising,” will be understood to imply the inclusion of a stateditem, element or step or group of items, elements or steps but not theexclusion of any other item, element or step or group of items. elementsor steps. Furthermore, the indefinite article “a” or “an” is meant toindicate one or more of the item, element or step modified by thearticle.

1. (canceled)
 2. A method comprising, in the following order: (a)detecting a baseline QTc of a subject; (b) administering a dose of aclass III antiarrhythmic drug to the subject via a first intravenousinfusion for a first duration of time; (c) detecting a second QTc of thesubject and determining a delta QTc from the difference between thesecond QTc measured after the first intravenous infusion and thebaseline QTc; and (d) determining whether the delta QTc is or is notwithin a specified range; wherein if the delta QTc is within thespecified range then (e) administering a further dose of the class IIIantiarrhythmic drug to the subject via a second intravenous infusion fora second duration of time, or administering at least one oral dose ofthe class III antiarrhythmic drug to the subject; or wherein if thedelta QTc is not within the specified range then (e) discontinuing thefirst intravenous administration and administering any further doses ofthe class III antiarrhythmic drug to the subject as an oral dose ordoses, or administering a reduced second intravenous dose or doses tothe subject.
 3. The method of claim 2, wherein the class IIIantiarrhythmic drug is sotalol.
 4. The method of claim 2, wherein theclass III antiarrhythmic drug is dofetilide.
 5. The method of claim 3,wherein the class III antiarrhythmic drug is amiodarone.
 6. The methodof claim 2, wherein the duration of time is 0.5 hour-2 hours.
 7. Themethod of claim 2, wherein the subject has normal or abnormal renalfunction and the dose of class III antiarrhythmic drug administered viathe intravenous infusion is 10 mg-80 mg.
 8. The method of claim 2,wherein the subject has normal or abnormal renal function, and whereinthe at least one oral dose of the class III antiarrhythmic drugcomprises 80 mg, 120 mg, or 160 mg.
 9. The method of claim 2, whereinthe subject has normal renal function and at least one of the oraldose(s) of the class III antiarrhythmic drug is administered at a12-hour interval from a previous oral dose.
 10. The method of claim 2,wherein the subject has abnormal renal function and at least one of theoral dose(s) of the class III antiarrhythmic drug is administered at a24-hour interval from a previous oral dose.
 11. A method comprising, inthe following order: (a) detecting a baseline QTc of a subject; (b)administering a dose of a class III antiarrhythmic drug to the subjectvia a first intravenous infusion for a first duration of time; (c)detecting a second QTc of the subject; wherein if the second QTc of thesubject prolongs to >500 msec, then (d) discontinuing the firstintravenous administration and administering any further doses of theclass III antiarrhythmic drug to the subject as an oral dose or doses,or administering a reduced second intravenous dose or doses to thesubject, or wherein if the further QTc does not prolong to >500 msec,then (d) administering at least one oral dose of the class IIIantiarrhythmic drug to the subject, or administering a secondintravenous infusion to the subject for a second duration of time. 12.The method of claim 11, wherein the class III antiarrhythmic drug issotalol
 13. The method of claim 11, wherein the class III antiarrhythmicis dofetilide.
 14. The method of claim 11, wherein the class IIIantiarrhythmic is amiodarone.
 15. The method of claim 11, wherein thesubject has normal or abnormal renal function and the dose of class IIIantiarrhythmic drug administered via the intravenous infusion is 10mg-80 mg.
 16. The method of claim 101, wherein the subject has normalrenal function and at least one of the oral dose(s) of the class IIIantiarrhythmic drug comprises 80 mg, 120 mg, or 160 mg.
 17. The methodof claim 11, wherein the subject has abnormal renal function and atleast one of the oral dose(s) of the class III antiarrhythmic drugcomprises 80 mg, 120 mg, or 160 mg.
 18. A method comprising, in thefollowing order: (a) detecting a QTc of a subject; (b) administering adose of a class III antiarrhythmic drug to the subject via a firstintravenous infusion for a first duration of time; (c) detecting asecond QTc of the subject; wherein if the further QTc of the subjectprolongs to >500 msec, then (d) discontinuing the first intravenousadministration and administering any further doses of the class IIIantiarrhythmic drug to the subject as an oral dose or doses oradministering a reduced second intravenous dose or doses to the subject,or wherein if the further QTc does not prolong to >500 msec, then (d)administering at least one oral dose of the class III antiarrhythmicdrug to the subject or administering a second intravenous infusion tothe subject for a second duration of time, wherein the subject achievessteady-state maximum plasma concentration within about 24 hours afterinitiation of administering the first intravenous infusion.
 19. Themethod of claim 18, wherein the class III antiarrhythmic drug issotalol.
 20. The method of claim 18, wherein the class IIIantiarrhythmic drug is dofetilide.
 21. The method of claim 18, whereinthe class III antiarrhythmic drug is amiodarone.
 22. The method of claim18, wherein the dose of class III antiarrhythmic drug administered viathe intravenous infusion is 10 mg-80 mg.
 23. The method of claim 18,wherein the at least one oral dose of the class III antiarrhythmic drugis in an amount of 80 mg, 120 mg, or 160 mg.
 24. The method of claim 23,wherein the at least one oral dose is administered at a 12-hour intervalor at a 24-hour interval from a previous oral dose.